Several articles have assessed the role of preoperative serum thyroglobulin (Tg) as predictor of malignancy of thyroid nodules, with particular focus on nodules with indeterminate cytology. However, the role of serum Tg as diagnostic marker remains unclear. The aim of the study was to perform a systematic review to add more evidence-based data on this topic. A comprehensive literature search was conducted to find relevant published articles on this topic. MeSH terms were: "thyroglobulin" and "predict*". In order to include only recent serum Tg assay methods, we analyzed the timeframe between 2001 and July 31(st), 2014. To expand our search, references of the retrieved articles were also screened. Thirteen studies, including 3,580 patients, were analyzed. Nine out of these studies reported data on thyroid nodules with prior indeterminate cytology. Preoperative serum Tg levels demonstrated suboptimal accuracy in discriminating malignant from benign nodules due to a significant overlap of values between these groups. However, most articles demonstrated a statistically significant difference in mean or median serum Tg between patients with cancer and benign lesions correlated to final histology. Furthermore, most studies reported Tg as independent predictor of malignancy. According to the most recent literature, the preoperative measurement of Tg alone fails to discriminate thyroid cancers from benign lesions. However, our data show that Tg is an independent predictor of malignancy; as a consequence, the presurgical determination of Tg should be considered in patients with thyroid nodules, especially when cytology is indeterminate.